Opioid receptors are mainly classified into three types, i.e., μ, δ and κ from a viewpoint of differences in pharmacological actions. On the basis of the discovery of an endogenous opioid peptide in 1970's, some progresses were made in studies about their mechanism of action. In 1990's, studies about opioid receptor structures advanced based on genetic analysis, and their mechanism of action has been being elucidated by the molecular biology. As also for the δ receptor, based on the success of cloning of δ receptor by Evans, Kieffer et al. in 1992, many studies have been vigorously performed in the medicinal and pharmaceutical fields by the molecular biology.
Although higher order functions of the opioid δ receptors have not yet been successfully elucidated, those already reported include that an opioid δ receptor agonist exhibits analgesic activity (D. E. Moulin et al., Pain, 1985, 23, 213), and that the opioid δ receptor agonist has an reducing effect on adverse reactions induced by an opioid μ receptor agonist and an opioid κ receptor agonist (Gallingan et. al., J. Pharm. Exp. Ther. 1984, 229, 641). Since the opioid δ receptor is known to be present widely in the central and peripheral nerve systems and considered to have a wide variety of functions, discovery of an effective and selective opioid δ receptor ligands can greatly contribute to therapeutic treatments of central nerve system diseases including schizophrenia, depression, cerebral apoplexy, epilepsy, Alzheimer's disease, and Parkinson's disease, and peripheral nerve system diseases including pains (Exp. Opin. ther. Patents, 1999, 9, 353).
Compounds related to the general formula (I) of the present invention are reported in J. Med. Chem. 1994, 37, 2125, WO93/15062, WO96/36620, WO97/10230, WO98/28270, WO98/28275 and the like. The compounds described in J. Med. Chem. 1994, 37, 2125 and WO93/15062 have very high affinity for δ receptors. However, these compounds have not been used clinically, because their productions are difficult due to three asymmetric centers, which are apparent from their chemical formulas, and they have poor pharmacokinetics. Derivatives having a structure with no asymmetric center are reported in WO96/36620, WO97/10230, WO98/28270, WO98/28275 and the like. However, their affinities for the δ receptor are undesirably lowered compared to the compounds described above. Thus, no compound has been reported which has a structure with no asymmetric center and high affinity for the δ receptor.
Further, the piperidine ring structure including R4, R5 and R6 of the general formula (I) of the present invention is already known. However, no compound has been reported which has these partial structure and high affinity for the δ receptor.